Niacin (also known as vitamin B3, nicotinic acid and vitamin PP) is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency (pellagra), vitamin C deficiency (scurvy), thiamin deficiency (beriberi), vitamin D deficiency (rickets), vitamin A deficiency (night blindness and other symptoms). Niacin has also been used to increase levels of HDL cholesterol in the blood, decrease levels of triglycerides in the blood, decrease levels of LDL in the blood, slow progression and, at times, cause regression of atherosclerotic plaque in arteries, and has been found to modestly decrease the risk of cardiovascular events and/or decrease cause of death in a number of controlled human trials.
Niacin administration, however, results in patients experiencing several side effects that have limited its widespread use. Most notably, the immediate release form of niacin (niacin IR) stimulates prostaglandin-mediated flushing of the face and trunk. The flush is usually felt within minutes (e.g., 15-20 minutes) after administration, but can stay for a period of days. In addition, the extended and sustained release (SR) forms cause the flushing reaction, although not to as great an extent. Patients experiencing the flushing side effect experience a diminution of symptoms over time and eventually develop a partial tolerance to the flushing, but not against the lipid-modifying effects. However, the level of discomfort is such that many patients stop therapy in the early period of treatment and never reach the tolerant stage. In addition, the typical dosing of niacin IR was three times per day, a factor that also contributed to low patient compliance.
Attempts have been made to mitigate the side effects of niacin IR, which is completely absorbed in 1-2 hours, with a sustained release form of niacin, i.e., niacin SR. The niacin SR, which requires a period of at least 12 hours for complete absorption, has met only modest success. It was observed that niacin SR was significantly less effective in modifying lipids than the IR form, and also was associated with an increased incidence of hepatotoxicity and gastrointestinal intolerance.
More recently, an intermediate or extended release form of niacin, niacin ER, has been developed that has an absorption rate in the 8-12 hour range. Niacin ER lowers the rate of flushing observed with niacin IR, and lowers the hepatotoxicity incidence seen with niacin SR. However niacin ER still has more hepatotoxicity and may have less efficacy than niacin IR.
It is known in the art that administering a non-steroidal anti-inflammation drug (NSAID), e.g., aspirin, from about 30 minutes to about 120 minutes prior to administering niacin IR can lower the flushing side effect. The dosing regimen of niacin IR, however, requires that it be taken three times per day, thereby requiring that a patient also take NSAID three times a day at specific time points. The need to take the medication six or more different time points is likely a major contributor to low compliance to niacin IR therapy.
Therefore, there is still a need to develop formulations that are effective in reducing or even eradicating the flushing side effect of niacin and at the same time helping patients to comply with the dosing requirements of the therapy.